(Behavioural Modification and Lorcaserin for Overweight and Obesity Management)1

The complications associated with obesity and overweight have received much press attention recently making this study by Smith et al.1 timely. That obesity and overweight are associated with significant cardiovascular mortality and morbidity is well recognised as is the fact that tackling the public health burden of these conditions will require a multi-faceted approach. It seems ironic therefore that some of the most promising drug therapies have been withdrawn because of cardiovascular side effects with sibutramine2 the most recent casualty leaving orlistat (now available over the counter) as the only licensed drug. Against this background alternative options in the therapeutic armoury would be very welcome. Lorcaserin is an agonist of the serotonin 2C (5-HT2c) receptor. Activation of this receptor decreases food intake via the proopiomelanocortin system of neurones. Fenfluraime and dexfenfluramine, which enhance presynaptic and block reuptake of serotonin, also work by this pathway but cause cardiac valvulopathy by their relative non-selectivity and agonism of 5-HT2B receptors found on cardiac tissue. Lorcaserin was designed to be more selective in terms of action, with a selectivity for central 5-HT2c receptors of 100 times that for 5-HT2B.

The BLOOM study was designed to evaluate the safety (predominantly effects on cardiac valves) and efficacy of lorcaserin used for weight management. 3182 (1595 lorcaserin, 1587 placebo) patients were randomly assigned to 10mg lorcaserin or placebo for the first year. At the end of this time those patients who were in the active group (883) were reassigned in a 2:1 ratio to either lorcaserin or placebo while the 716 patients who were taking placebo continued to do so. Patients were seen at baseline, 2 and 4 weeks and then on a monthly basis. At each visit patients were instructed to undertake 30 minutes of moderate exercise daily and to reduce calorie intake to 600kcal below estimated requirements in addition to receiving between 15 and 60 minutes of nutritional and exercise counselling. The baseline characteristics of both groups were very similar with >80% females in both groups and an average body mass index of 36.2 kg/m2 (an average weight of 100kg in real terms). There was however a relatively high dropout rate in both arms with 55.4% of the active and 45.1% of the study group completing 1 year follow-up (6-7% of patients discontinued because of adverse events, headache and dizziness being more common in the study group). At the end of the first year 47.5% of subjects in the active group and 20.3 % of subjects in the placebo group had lost more than 5% of their baseline weight corresponding to an average loss of 5.8 +/- 0.2 kg versus 2.2 +/- 0.1 kg (p<0.001). Of these patients those who continued to receive lorcaserin in year 2 a greater proportion maintained their weight loss (67.9 vs 50.3%, p<0.001). Fasting glucose, insulin, total cholesterol and triglycerides were significantly lower in the lorcaserin group at year 1 but all these measures tended to increase towards the placebo group by the end of year 2. At the end of year 1 valvulopathy (ie moderate or more sever mitral regurgitation or at least mild aortic regurgitation) had developed in 2.3% of the placebo group and 2.7% in the treatment group with the corresponding figures being 2.7% and 2.6% at the end of year 2.

What does this study tell us? Although the weight loss achieved in this study is modest, previous studies show us that losing 5-10% of body weight has beneficial effects on hypertension,sleep apnoea and the development of type 2 diabetes and heart disease. Lorcaserin seems promising in the prevention of cardiovascular disease particularly given the improvements in serum lipids and blood pressure. However, as the incidence of valvulopathy (the primary end-point of the study) was only half of that expected the statistical power of the study to rule out a relative risk with lorcaserin of 1.5 is 60% meaning that the cardiovascular safety of this drug is not yet clear. What is also clear from this study where multiple interventions were used to try to maximise weight loss is that there is no magic solution to the problem and that maintenance of weight loss needs as much focus as the initial loss. What role lorcaserin will play in the future is not clear and whether the beneficial cardiovascular effects will predominate remains to be determined.